Preterm birth remains the leading cause of perinatal morbidity and mortality after congenital birth defects affecting 1 of every 8 pregnancies. Cervical shortening has been recognized as a major risk factor for preterm birth. Shortening is likely to represent premature loss of normal mechanical function. The cervix has been recognized as a potential target for therapeutic intervention but little is known about its regulation. The principal function of the cervical extracellular matrix is to maintain the pregnancy in utero. The cervix undergoes biochemical changes during pregnancy that reduces its ability to resist mechanical forces that are thought to be mediated by both the hormonal environment and mechanical stress. The transforming growth factor 2 (TGF2) signaling pathway controls many tissue remodeling processes. Hormones and mechanical force have been shown to alter TGF2 signaling. The goal of this project is to determine the role of TGF2 in cervical matrix production during pregnancy. Three specific aims are identified: 1.) To determine the effects of TGF2 signaling on extracellular matrix metabolism within cervical stromal cells;2.) To determine the effects of hormonal environment (Estrogens, Progestins, and Androgens) on TGF2 signaling leading to changes in cervical collagen metabolism;and 3.) To determine the role of mechanical strain on cervical extracellular matrix production. Molecular and biomechanical techniques will be used to evaluate the role of TGF2 signaling on extracellular matrix production. The effects of both hormonal environment and mechanical stress on TGF2 signaling will be investigated. By identifying key regulatory elements responsible for cervical extracellular matrix remodeling, interventions can be developed and tested to prevent cervical failure and preterm birth. PUBLIC HEALTH RELEVANCE: Preterm birth is a major contributor to learning disabilities and physical handicaps. The goal of this proposal is to identify new targets for therapeutic intervention that relate to cervical function and extracellular matrix remodeling. The cervical extracellular matrix is responsible for its primary mechanical function of maintaining the pregnancy to term.